The innate immune system represents an important cellular component at the maternal-fetal interface and it is critical for the survival of the fetus. Our overall hypothesis is that the innate immune system is necessary for normal pregnancy by supporting i) trophoblast implantation/invasion, ii) vascularization and iii) host protection. We propose that the cellular component at the implantation site communicate with each other throughout a network of cytokines/chemokines. Such crosstalk occurs through the expression of specific receptors, known as Toll-Like Receptors (TLRs), which may direct and coordinate this cytokine/chemokine network. Our central hypothesis is that TLRs expressed at the maternal-fetal interface serve as sensors for the recognition and response to the environment throughout implantation and gestation. Our main goal is to determine and characterize the specific role of TLRs during pregnancy. In this program application, three groups of investigators from the Department of Obstetrics, Gynecology and Reproductive Sciences at Yale University School of Medicine will evaluate the role of TLRs in the interactions between trophoblast cells, decidual cells (stromal/endothelial) and innate immune cells. Furthermore, the program will investigate the role of TLRs in, trophoblast invasion, spiral artery transformation and host protection during the first trimester of pregnancy and at term. The three groups have extensive experience in placental/uterine biology and reproductive immunology. In Project I. (Mor/Abrahams) will test the hypothesis that the trophoblast controls the presence and function of the innate immune system at the implantation site by responding to the maternal environment through the expression of TLRs. Project II. (Lockwood/Krikun) will test the hypothesis that the activation of TLRs expressed by decidual stromal and innate immune cells plays a role in promoting trophoblast invasion and transformation of spiral arteries. Project III. (Guller/Norwitz) will test the hypothesis that cross-talk between TLR and GR-dependent signaling pathways in placental syncytiotrophoblast (SCT) and fibroblasts (FIBs) protects the fetus against microbial compounds while limiting inflammation at this site.